The Neuropathology Core (NP Core) will play an active and critical role in therapeutic trials of quinacrine and the discovery and testing of new therapeutic agents. (1) It has the traditional role of making the definitive diagnosis of CJD and related disorders from brain biopsies during life and in autopsied brain after the death of a patient. (2) The NP Core will assess the benefits of treatment protocols including quantifying the degree of clearance of PrP(Sc) and the degree of abatement of the most clinically relevant neuropathological changes, i.e. vacuolar degeneration of neurons, loss of presynaptic boutons, atrophy of dendritic trees, and loss of nerve cells. (3) The NP Core will determine the biological basis of treatment failures by performing a full autopsy to determine the immediate cause of death and unbiased quantification of synapse and neuron numbers in critical CNS regions to determine whether clearance of PrP(Sc) halted programmed death pathways that were triggered by PrP(Sc) accumulation in neurons before treatment was started. (4) The NP Core will test for adverse drug reactions including the possibility that a therapeutic agent combines with CJD pathogenic mechanisms to facilitate neurodegeneration. To accomplish these goals, two levels of neuropathological analysis of human CJD cases and animal models of prion disease are proposed. First, traditional neurohistopathological and immunohistochemical methods that have been the mainstay of past NP Cores will be used to assess the degree of PrP(Sc) loss and degree of abatement of spongiform degeneration, reactive astrocytic gliosis, and reactive microgliomatosis, Second, advanced quantitative neuropathological techniques, including unbiased stereology and Golgi silver impregnation of dendritic trees, will be developed to obtain accurate counts of synaptic boutons and nerve cell bodies and to determine the degree of atrophy of neuronal dendritic trees. These parameters are the best measures of the success or failure of a treatment protocol. Results will be correlated with the cognitive and neurological states of patients. Interestingly, the data from one Creutzfeldt-Jakob disease (CJD) patient treated with quinacine suggest that treatment may have decreased the total PrP so load and accompanying neuropathological changes.